A number of drugs contain chiral centers and thus can exist in two or more isomeric forms. A drug with a single chiral center can be formed as two "mirror-image" isomers, known as "enantiomers." In many instances, the enantiomers exhibit differences in pharmacokinetic properties, e.g., metabolism, protein binding, or the like, and/or pharmacological properties, e.g., the type of activity displayed, the degree of activity, toxicity, or the like. Isolation of a single enantiomer from a mixture, i.e., "resolution" of the mixture, is typically carried out by reaction with a standard asymmetric substance, followed by separation of the different products using conventional means. Fractional crystallization is another technique which may be employed to isolate a single enantiomer. Frequently, however, isolation of a single enantiomer from a mixture is difficult, as the two enantiomers within the mixture are by definition identical in terms of molecular composition and thus, in many instances, are substantially similar in reactivity. Alternatively, a single enantiomer of a drug or other compound may be prepared using a stereospecific synthesis which gives rise to the product in enantiomerically pure form. Such syntheses are typically somewhat difficult to implement and often do not provide the desired product in high yield.
Recent reports detail the lengths undertaken in order to obtain purified isomers of useful drugs. For example, U.S. Pat. No. 5,545,745 to Gao et al. claims a multistep process for preparing optically pure albuterol, employing reaction of a mixture of albuterol isomers with a chiral acid and selective crystallization of one of the products, followed by debenzylation to yield optically pure albuterol. U.S. Pat. No. 5,442,118 to Gao et al. claims a method of asymmetric synthesis of (R) and (S) arylethanolamines from aminoketones, useful for the preparation of pharmaceutical agents such as albuterol, terbutaline, isoproterenol and sotalol, using a borane reducing agent in the presence of a chiral 1,3,2-oxazaborolidine catalyst, wherein the reagents must be added in a specific order. U.S. Pat. No. 5,516,943 to Gao et al. describes the stereoselective conversion of a trans-1-amino-2-hydroxycycloalkane to the cis isomer by acylating the amine group and then treating with a strong acid; also disclosed is the direct formation of particular isomers of aminoindanol from indene using exotic chiral catalysts. U.S. Pat. No. 5,498,625 to Evans et al. describes the enzymatic production of one enantiomer of a lactam by reacting a racemic .gamma. lactam with a stereospecific lactamase. U.S. Pat. No. 4,800,162 to Matson claims a method of resolving a racemic mixture by passing a solution containing the mixture through a filtering device having a stereoselective enzyme attached to the filter matrix on a first side: the enzyme selectively reacts with one isomer, creating a product which is then more soluble in an immiscible solvent flowing in the opposite direction on the opposite side of the matrix; the product then diffuses across the matrix, yielding a pure solution of enantiomeric product on the opposite side and producing a pure solution of the unreacted enantiomer on the first side.
As can be seen, elaborate efforts have been made in order to produce purified isomers of pharmacologically active agents.
With chiral drugs, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body as compared with the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug, or to a lower amount of a toxic isomer. Costly and complicated stereospecific synthesis or purification schemes would then be unnecessary.
Accordingly, there is a need in the art for a means of drug administration which enables preferential delivery of a single enantiomer of a chiral drug.
International Patent Publication No. WO 94/10985 describes the benefits provided by transdermal delivery of the active enantiomer of ketorolac compared to delivery of the racemic mixture. The active enantiomer was found to have a more rapid clearance than the other enantiomer, so that the continuous delivery provided by a transdermal system allowed for even lower dosages to be used than expected. That is, whereas one might expect that half of the total amount of the pure enantiomer would be as effective as the full dose of the racemic mixture, even less than half the amount of the pure enantiomer was found to be effective. This was attributed to the more rapid clearance and shorter half-life of the active enantiomer. Continuous delivery using the passive transdermal system provided a more steady level of the minimum therapeutic amount of the active enantiomer as compared with periodic dosing of the racemic mixture by immediate release oral or parenteral administration. Passive transdermal delivery was claimed to be beneficial for all enantiomers with high clearance values and short half-lives. Problems with passive transdermal drug delivery systems were also discussed, including the limits on the doses capable of being provided because of the limited permeability of the stratum corneum layer of the skin and the unacceptability of large patches to patients because of contact-related side effects, aesthetics, comfort and wearability.
The melting temperature of a drug is believed to be one factor limiting the ability of that drug to permeate the skin. Lawter and Pawelchak (U.S. Pat. No. 5,114,946) claimed that, for a chiral drug that is a solid at or above skin temperature, purified enantiomers or nonracemic mixtures of the drug display faster passive transdermal delivery rates when the purified enantiomers or the nonracemic mixtures have melting temperatures 5.degree.-10.degree. C. below that of the racemic mixture. However, no increase in the flux rate of one isomer relative to the other isomer in a mixture was noted.
Sanderson (U.S. Pat. No. 4,818,541) similarly reported that the purified individual isomers of phenylpropanolamine gave rise to faster transdermal penetration rates compared to the racemic mixture. The mechanism by which this occurred was not stated with certainty, but the increased solubility of the individual isomers compared to the mixture was suggested as one possibility. Each of the four individual purified isomers exhibited nearly identical flux rates.
The inventors herein have now found that passive transdermal drug delivery of a composition containing a drug (ketorolac) in the form of a racemic mixture does not provide for any significant difference in flux between the two isomers. This is consistent with previous reports that (-) ketorolac and racemic ketorolac have similar flux characteristics when used in several different types of passive transdermal systems (U.S. Pat. No. 5,589,498 to Mohr et al.). (-) Ketorolac is the active enantiomer of ketorolac, a non-steroidal anti-inflammatory analgesic which can produce gastrointestinal side effects when delivered orally. Transdermal patches of the adhesive matrix type, reservoir type, and monolithic matrix type were all reported to deliver similar flux rates of (-) ketorolac and racemic ketorolac.
Unexpectedly, electrotransport drug delivery has been discovered to give rise to a substantial differential in the rate of transport of two enantiomers contained in a mixture. Prior to applicants' invention, it was believed that the capability of administering a drug using electrotransport was solely a function of the drug's physico-chemical properties; now, it is clear that electrotransport drug delivery can be stereospecific as well.
In contrast to passive transdermal or transmucosal systems, electrotransport has been found to provide for the preferential delivery of one isomer from a mixture while providing a faster overall flux rate than passive delivery systems, and requires no special synthetic or purification schemes. Additionally, preferential isomer delivery via electrotransport is not limited to particular mixtures of drug isomers that have a lower melting temperature than the racemic mixture, or to enantiomers with high clearance values and low half-lives. As a result of the increased transfer rate, electrotransport can permit a shorter time of delivery or the use of a smaller, more acceptable coverage area in order to deliver the desired amount of compound than such passive delivery systems. Generally, it is preferred that at least a 20% increase in the rate of in vivo delivery of the preferred isomer is achieved. However, a smaller increase in rate of delivery, of about 5 or 10%, may prove acceptable in some cases, for example where the drug is particularly expensive.
By eliminating the need for stereospecific synthesis or complicated purification procedures, selective delivery of one isomer via electrotransport can lead to improvements in therapeutic costs and treatment regimens. Costs of synthesis can be decreased by eliminating the need for stereospecific synthesis or purification of one isomer from a mixture. A simpler scheme for synthesis and purification can result in a lowered generation of hazardous materials and a lessened exposure of personnel to those materials. Additionally, stereoselective electrotransport can be used to preferentially deliver one isomer where stereospecific synthesis or purification of that isomer has not yet been achieved. By receiving an increased amount of the preferred isomer, patients can thus be exposed to a lesser total amount of compound or be treated for a shorter time or over a smaller region of their body.
Furthermore, even if passive drug delivery could give rise to differences in flux rates of desired isomers, electrotransport can increase this differential while providing higher overall flux rates than passive systems, allowing for smaller, more acceptable delivery devices. Similarly, where chemical synthesis or purification schemes provide a greater proportion of the desired enantiomer in a mixture, electrotransport delivery of the mixture can further increase the proportion of desired enantiomer which is delivered.
Herein the term "electrotransport drug delivery" is used to refer to the delivery of pharmaceutically active agents through an area of the body surface by means of an electromotive force to a drug-containing reservoir. The drug may be delivered by electromigration, electroporation, electroosmosis or any combination thereof. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically induced osmosis. In general, electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species. During the electrotransport process, certain modifications or alterations of the skin may occur such as the formation of transiently existing pores in the skin, also referred to as "electroporation." Any electrically assisted transport of species enhanced by modifications or alterations to the body surface (e.g., formation of pores in the skin) are also included in the term "electrotransport" as used herein. Thus, as used herein, the term "electrotransport" refers to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.